One of the hallmarks of cancer development is the loss of cellular growth control. We have reported on the induction of in vitro growth arrest of MCF7 breast cancer cells following the transfer of a normal chromosome 17 by microcell mediated chromosome transfer (MMCT). They hypothesize that they have identified a novel growth suppressor gene that may be involved in cancer development, and that growth suppression occurs through a previously described mechanism, such as the induction of cellular senescence apoptosis or differentiation. Since their last submission, they have made substantial progress towards identifying the MCF7 growth suppressor gene. They have mapped it to a 530kb region on chromosome 17q24 by MMCT, thereby excluding the p53 and BRCA1 genes. We have completed both PAC and YAC contigs, and have to date identified five candidate genes. One of these candidates may be the human homologue of IMP2, a mitochondrial intermembrane signal peptidase believed to be important in the induction of apoptosis. High throughput sequence analysis of two thirds of the PACs suggests that only a limited number of genes lies in this region. They have found that the induction of in vitro growth suppression by chromosome 17 is not unique to MCF7 cells, and in fact induces growth arrest in the majority of cancer cell lines tested. They have shown that the growth arrest of these cell lines is induced by a gene mapping to the same region as the MCF7 growth suppressor gene, implying that inactivation of a gene(s) in this region may be essential for the initiation or maintenance of many cancer cell lines in culture. In this competing renewal, they describe their strategy for the cloning and characterization of the MCF7 growth suppressor gene, and for determining its role in normal cell growth and tumor development. The Specific Aims of this proposal are: 1) to complete the transcript map of the 530kb growth suppressor gene region; 2) to characterize the MCF7 growth suppressor gene; and 3) to determine the mechanism of MCF7 growth arrest and the biochemical role of the MCF7 growth suppressor gene in the cell. The overall goals of this study are to understand mechanisms of growth suppression, and to evaluate the role of these mechanisms in cancer development.